Hormone Receptor Positive Breast Cancer

Possible Side Effects Of Ais

The most common side effects of AIs are:

• Hot flashes
• Bone and joint pain
• Muscle pain

AIs tend to have side effects different from tamoxifen. They don’t cause uterine cancers and very rarely cause blood clots. They can, however, cause muscle pain and joint stiffness and/or pain. The joint pain may be similar to a feeling of having arthritis in many different joints at one time. Options for treating this side effect include, stopping the AI and then switching to a different AI, taking a medicine called duloxetine , or routine exercise with nonsteroidal anti-inflammatory drugs . But the muscle and joint pain has led some women to stop treatment. If this happens, most doctors recommend using tamoxifen to complete 5 to 10 years of hormone treatment.

Because AIs drastically lower the estrogen level in women after menopause, they can also cause bone thinning, sometimes leading to osteoporosis and even fractures. If you are taking an AI, your bone density may be tested regularly and you may also be given bisphosphonates or denosumab , to strengthen your bones.

Questions To Ask Your Doctor

To learn more about estrogen and progesterone receptor testing for breast cancer, consider asking your doctor the following questions:

• What are the results of the ER and PR tests on my tumor sample? What do they mean?

• Does this laboratory meet the standard guidelines like those from ASCO and the CAP?

• Has a board-certified pathologist diagnosed my cancer?

• Do you know if this is an experienced lab and if my tissue was quickly given to the pathologist after my biopsy or surgery, as recommended by guidelines?

• Can I obtain a copy of my pathology report ?

• Is my ER and PR status indicated on the pathology report? Was the ASCO-CAP guideline recommendation used to define the status?

• Based on these test results, what treatments do you recommend and why?

• What are the possible side effects of these treatments?

How Is Hormone Therapy Used To Treat Breast Cancer

There are three main ways that hormone therapy is used to treat hormone-sensitive breast cancer:

Adjuvant therapy for early-stage breast cancer:Tamoxifen is FDA approved for adjuvant hormone treatment of premenopausal and postmenopausal women with ER-positive early-stage breast cancer, and the aromatase inhibitorsanastrozole, letrozole, and exemestane are approved for this use in postmenopausal women.

Research has shown that women who receive at least 5 years of adjuvant therapy with tamoxifen after having surgery for early-stage ER-positive breast cancer have reduced risks of breast cancer recurrence, including a new breast cancer in the other breast, and reduced risk of death at 15 years .

Until recently, most women who received adjuvant hormone therapy to reduce the chance of a breast cancer recurrence took tamoxifen every day for 5 years. However, with the introduction of newer hormone therapies , some of which have been compared with tamoxifen in clinical trials, additional approaches to hormone therapy have become common .

Some premenopausal women with early-stage ER-positive breast cancer may have ovarian suppression plus an aromatase inhibitor, which was found to have higher rates of freedom from recurrence than ovarian suppression plus tamoxifen or tamoxifen alone .

Men with early-stage ER-positive breast cancer who receive adjuvant therapy are usually treated first with tamoxifen. Those treated with an aromatase inhibitor usually also take a GnRH agonist.

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Progesteronepr Signaling Klf5 And Breast Cancer

Progesterone is essential for normal postnatal mammary gland development during pregnancy and lactation by stimulating ductal side branching and development of lobuloalveolar structures . A recent study showed that progesterone promotes proliferation and activity of mammary stem cells . In addition, PR knockout mice showed incomplete mammary gland ductal side branching due to insufficient cell proliferation .

Accumulated evidence suggests that Pg and PR promote mammary tumorigenesis . Administration of medroxyprogesterone acetate, a synthesized progesterone, induces mammary ductal carcinomas with a mean latency of 52 weeks and an incidence of about 80% in BALB/c female mice . Moreover, Pg has been shown to increase breast cancer risk for menopausal women in several large-scale hormone-replacement therapy clinical studies . In these studies, Pg plus estrogen significantly increased the risk of invasive breast cancer compared with estrogen alone. Additionally, Pg has been shown to have proliferative effects in the PR-positive breast cancer cell lines in vitro and in nude mice . Importantly, Pg was shown to reprogram a small subset of ER +/PR +/cytokeratin 5 -differentiated luminal cells into ERPRCK5 + progenitor cancer cells .

Taken together, these findings suggest that KLF5 is an important downstream target gene of the PgPR signaling to regulate the development of normal breast and breast cancer.

Yikyung Park, in, 2019

What Are The Side Effects Of Hormone Therapy

The side effects of hormone therapy depend largely on the specific drug or the type of treatment . The benefits and harms of taking hormone therapy should be carefully weighed for each person. A common switching strategy used for adjuvant therapy, in which patients take tamoxifen for 2 or 3 years, followed by an aromatase inhibitor for 2 or 3 years, may yield the best balance of benefits and harms of these two types of hormone therapy .

Hot flashes, night sweats, and vaginal dryness are common side effects of all hormone therapies. Hormone therapy also may disrupt the menstrual cycle in premenopausal women.

Less common but serious side effects of hormone therapy drugs are listed below.

Tamoxifen

• breathing problems, including painful breathing, shortness of breath, and cough
• loss of appetite

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Can Hormone Therapy Be Used To Prevent Breast Cancer

Yes. Most breast cancers are ER positive, and clinical trials have tested whether hormone therapy can be used to prevent breast cancer in women who are at increased risk of developing the disease.

A large NCI-sponsored randomized clinical trial called the Breast Cancer Prevention Trial found that tamoxifen, taken for 5 years, reduces the risk of developing invasive breast cancer by about 50% in postmenopausal women who were at increased risk . Long-term follow-up of another randomized trial, the International Breast Cancer Intervention Study I, found that 5 years of tamoxifen treatment reduces the incidence of breast cancer for at least 20 years . A subsequent large randomized trial, the Study of Tamoxifen and Raloxifene, which was also sponsored by NCI, found that 5 years of raloxifene reduces breast cancer risk in such women by about 38% .

As a result of these trials, both tamoxifen and raloxifene have been approved by the FDA to reduce the risk of developing breast cancer in women at high risk of the disease. Tamoxifen is approved for this use regardless of menopausal status. Raloxifene is approved for use only in postmenopausal women.

Hormone Receptor Positive Breast Cancer

Your breast cancer may be hormone receptor-positive or HR+. Some breast cancers have receptors on them that attach to the hormones, estrogen, and progesterone, as they circulate in your body. These hormones feed the cell and help it grow.

• If your tumor has hormone receptors, it is called hormone receptor-positive or HR+. If your tumor is HR+, the tumor needs estrogen and/or progesterone to grow.
• About 80% of breast cancers are HR+.
• If your tumor does not have hormone receptors, it is hormone receptor-negative or HR-.

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Hormone Receptors & Receptor Tests

All breast cancers are examined under a microscope for biomarkers of estrogen and progesterone receptors. About 70% of breast cancers are hormone receptor-positive.

Your hormone receptor status should appear on your pathology report after biopsy or surgery. Receptors will be retested if you ever have a recurrence or metastases as well, as your status can change.

Hormones and receptors go together kind of like a lock and key. Receptors are proteins on the surface of breast cells, and when hormones bind to them, the receptors tell the cells to grow and divide. All breast cells have receptors, but they are found in much greater numbers on breast cancer cells that are considered positive.

A goal of treatment is to block the signal created when the hormones attach to receptors. Doing that requires one of two things:

Most of the time, breast cancers tend to be positive or negative for both estrogen and progesterone receptors. Now and then, one will be positive for estrogen but not progesterone. The treatment is the same either way.

Breast Cancer Hormone Receptor Status

Breast cancer cells taken out during a biopsy or surgery will be tested to see if they have certain proteins that are estrogen or progesterone receptors. When the hormones estrogen and progesterone attach to these receptors, they stimulate the cancer to grow. Cancers are called hormone receptor-positive or hormone receptor-negative based on whether or not they have these receptors . Knowing the hormone receptor status is important in deciding treatment options. Ask your doctor about your hormone receptor status and what it means for you.

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From The 2005 San Gallen Conference Onwards: Conceptual Evolution Of Adjuvant Therapy For Hormone

The hypotheses on the marginal role of adjuvant chemotherapy in the treatment of hormone receptor-positive early breast cancer were the foundation of a shift in the paradigm of treatments choices. At the 2005 San Gallen Conference panelists proposed an alternative approach to previously followed one, which called for risk estimation as the initial step in the decisional process .

In the following chapters, we will discuss whether this assumption is acceptable in the light of the most recent results of adjuvant chemotherapy studies.

How Are Hormone Receptor

HR+ breast cancers can be treated with endocrine therapy to block the action of hormones. These therapies may be used alone or in combination with chemotherapy, targeted therapy, surgery, and radiation.

• Hormone therapies for HR+ breast cancers include aromatase inhibitors , selective estrogen receptor modulators , and estrogen receptor antagonists .
• In early-stage breast cancer, hormone therapies may be used along with chemotherapy and targeted therapy such as Herceptin, if the tumor is also HER2 positive.
• In these cases, hormone therapy may be taken for 5-10 years after completing the initial chemotherapy treatment.
• In more advanced HR+ breast cancers, hormone therapies are often used in combination with targeted therapies including lapatinib, palbociclib, and ribociclib.
• You may take one hormone therapy for a while and then it stops working. Your provider may then give you a different hormone therapy.
• Removing or suppressing the ovaries, puts a pre-menopausal woman into menopause. This shuts down the production of estrogen by the ovaries. Medications used for ovarian suppression are called gonadotropic-releasing hormone analogs, such as goserelin acetate and leuprolide. These medications may be used in combination with other hormone therapies. The ovaries can also be surgically removed in a procedure called an oophorectomy. This can impact fertility, so be sure to talk with your healthcare provider about fertility preservation before starting these therapies.

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Treatment For Pr Positive Breast Cancer

Most PR positive breast cancers are also ER positive, and you may be offered hormone therapy.

The benefits of hormone therapy are less clear for people whose breast cancer is only PR positive. Very few breast cancers fall into this category, but if this is the case your specialist will discuss with you whether hormone therapy is suitable.

Qol Considerations In Visceral Disease

The QoL of patients with BC is impacted by the effectiveness and AE profile of the therapeutic intervention, and it is well-established that treatment-related toxicities can adversely affect the QoL of patients with ABC.67 For instance, chemotherapy can cause serious AEs, such as nausea, vomiting, myelosuppression, and infectious complications, as well as symptom clusters, such as insomnia, mood disturbances, pain, and fatigue 8,22,24,67 and AIs can cause hot flashes, arthralgia, vaginal dryness, and dyspareunia,6,22,68,69 all of which can negatively affect QoL. Because treatment-related toxicity and painful visceral metastases can have a major impact on QoL, any new treatments or treatment regimens should, in addition to any clinical benefits, provide palliation and maximize QoL.67

The QoL results from BOLERO-2 provide additional support for the benefit of everolimus plus exemestane in patients with ABC in whom disease progressed after treatment with nonsteroidal AIs. Further studies are needed that evaluate HRQoL for new treatment regimens currently being investigated in endocrine-resistant HR+ ABC.

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Epidemiology Of Breast Cancer

Globally, breast cancer is the most common cancer in women and the second most common cancer in the world. More than 1.67 million new breast cancer cases were diagnosed in 2012 . Incidence rates range from 27 per 100,000 in developing areas to 92 in more developed areas .4 Several epidemiologic studies have linked these different rates to reproductive and breastfeeding differences5 in addition to lower screening rates and incomplete reporting.6 If women in developed countries had the average number of births and lifetime duration of breastfeeding that women in developing countries have had until recently, the cumulative incidence of breast cancer would be reduced by more than half, from 6.3 to 2.7 per 100 women by age 70. The protective effect of parity was restricted to estrogen receptor -positive/progesterone receptor -positive breast cancer with each birth reducing the risk of ER-positive PR-positive cancer by 11% .7

Even though incidence rates are much lower in developing countries, mortality rates are practically equal across the world due to less favorable health conditions and limited access to care in the developing countries .4 Worldwide, the incidence of breast cancer has been going up in most regions but at faster rates in developed than developing countries. Trends in mortality from breast cancer, however, show steady decrease in most developed countries and stagnation or slight increase in developing countries.4

JoEllen Welsh, in, 2017

Hormone Therapy For Breast Cancer

Some types of breast cancer are affected by hormones, like estrogen and progesterone. The breast cancer cells have receptors that attach to estrogen and progesterone, which helps them grow. Treatments that stop these hormones from attaching to these receptors are called hormone or endocrine therapy.

Hormone therapy can reach cancer cells almost anywhere in the body and not just in the breast. It’s recommended for women with tumors that are hormone receptor-positive. It does not help women whose tumors don’t have hormone receptors .

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Genomic And Transcriptomic Profiling

CIBERSORT is a computational method that quantifies the proportion of 22 functional immune subsets within bulk tissue gene expression profiles. Ali and colleagues used CIBERSORT to analyze bulk gene expression profiles of 10,988 breast tumors from 56 publicly available datasets . Specifically, this study aimed to determine the relationship between TME composition and molecular subtype, survival and response to chemotherapy. In HR+ tumors, the presence of M0 macrophages and regulatory T cells were associated with poor prognosis , which was later confirmed by another group studying the prognostic significance of tumor-infiltrating immune cells in breast cancer . Notably, the HR+ tumors lacking immune infiltration were associated with intermediate or similar survival outcomes compared to HR+ tumors with high or low immune infiltrates. Thus, in this large cohort, the presence of immune cells was not prognostic of outcome in HR+ breast tumors .

If Cancer Comes Back Or Has Spread

AIs, tamoxifen, and fulvestrant can be used to treat more advanced hormone-positive breast cancers, especially in post-menopausal women. They are often continued for as long as they are helpful. Pre-menopausal women might be offered tamoxifen alone or an AI in combination with an LHRH agonist for advanced disease.

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What This Means For Patients

Because the results of ER and PR testing can make a difference in a persons treatment and chance of recurrence, it’s important that these tests are accurate. This guideline was developed to help both doctors and laboratories know how to improve the accuracy of ER and PR testing for those with breast cancer. Understanding the ER/PR status of the primary tumor and any distant or recurrent tumors can help doctors make sure that patients receive the appropriate treatment and avoid side effects of a treatment that may not work. Use this guideline to talk with your doctor about the accuracy of your ER and PR test results and what that means for your treatment.

How Does Hormone Therapy Work

About 2 out of 3 breast cancers are hormone receptor-positive. Their cells have receptors for estrogen and/or progesterone which help the cancer cells grow and spread.

There are several types of hormone therapy for breast cancer. Most types of hormone therapy either lower estrogen levels in the body or stop estrogen from helping breast cancer cells grow.

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Mirna And Extracellular Vesicles

MicroRNAs are small regulatory non-coding RNA molecules and miRNA deregulation was first reported in 2005 in BC . Investigators have reported that miRNAs can regulate the network/cascade of signal transduction pathways associated with endocrine resistance by several mechanisms: upregulating drug efflux transporters and anti-apoptotic proteins, promoting EMT and forming cancer stem cells .

Extracellular vesicles derived from cancer cells are similar to lipid vesicles, and contain oncogenic material in the form of overexpressed oncogenic genes/proteins/mediators/nucleic acids/non-coding RNA’s and metabolic enzymes. They typically home into specific recipient cells where they can trigger a separate cascade of molecules and associated pathological response . An analysis of the contents within the EV could shed light on their role in endocrine resistance and metastasis. EVs have been implicated in transmitting tamoxifen resistance from the TAM resistant cells to the TAM sensitive cells via the EVs containing miR-221/222 . Cancer biomarkers identified include HER2 and HLA-G, which is associated with circulating tumor cells and promotes proliferation, therapy resistance and metastasis . The translational capacity of miRNAs and EVs hold promise toward identifying therapies to combat endocrine resistance.